A locus for juvenile myoclonic epilepsy maps to 2q33–q36

We performed a whole genome linkage analysis in a three-generation south Indian family with multiple members affected with juvenile myoclonic epilepsy (JME). The maximum two-point LOD score obtained was 3.32 at recombination fraction (θ ) = 0 for D2S2248. The highest multipoint score of 3.59 was observed for the genomic interval between D2S2322 and D2S2228 at the chromosomal region 2q33–q36. Proximal and distal boundaries of the critical genetic interval were defined by D2S116 and D2S2390, respectively. A 24-Mb haplotype was found to co-segregate with JME in the family. While any potentially causative variant in the functional candidate genes, SLC4A3, SLC23A3, SLC11A1 and KCNE4, was not detected, we propose to examine brain-expressed NRP2, MAP2, PAX3, GPR1, TNS1 and DNPEP, and other such positional candidate genes to identify the disease-causing gene for the disorder

An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene

Objective: To identify the disease locus in a three-generation south Indian family having several of its members affected with idiopathic epilepsy. Methods: Genome-wide parametric linkage analysis was performed with 382 autosomal markers. Mutational analysis of the positional candidate genes in linked interval was performed by direct sequencing of genomic DNA from the proband in the family. Expression analysis in human adult brain was performed by Western blotting. Results: A novel epilepsy genetic locus on chromosome 3q13.3-q21 was identified by linkage analysis. This locus comprises about 12 megabases of the genomic interval, with its proximal and distal genetic boundaries defined by microsatellite markers, D3S3675 and D3S1551, respectively. In this interval, we found a novel, patient-specific, missense variant, Arg898Gln, at the extracellular calcium sensing receptor (CASR), a gene belonging to the G-protein-coupled receptor family. CASR expression was detected in the temporal lobe, frontal lobe, parietal lobe, cerebellum, and hippocampus. Four additional, potentially pathogenic, missense CASR variants, Glu354Ala, Ile686Val, Ala988Val, and Ala988Gly, were observed in five individuals affected with idiopathic generalized epilepsy. Interpretation: A novel idiopathic epilepsy locus has been mapped on chromosome 3q13.3-q21, as evident by presence of significant genetic linkage. Identification of novel, rare missense CASR variants at evolutionary-conserved residues in epilepsy patients and CASR expression in various subregions of human brain raises an interesting possibility of involvement of CASR in pathophysiology of epileptic disorders